Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A macaque's-eye view of human insertions and deletions: differences in mechanisms.

ABSTRACT: Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.

SUBMITTER: Kvikstad EM

PROVIDER: S-EPMC1976337 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Human gene targeting favors insertions over deletions.

Project description:Gene targeting is a powerful technique for manipulating the human genome, but few studies have directly compared the targeting frequencies of various types of vector constructs. Here we show that similar targeting constructs are able to insert nucleotides at the homologous chromosomal target locus more efficiently than they can delete nucleotides, and combination insertion/deletion vectors appear to target at intermediate frequencies. This holds true for deletions ranging from 1 to 334 bp and insertions ranging from 1 to 1332 bp. In addition, vectors designed to inactivate the human hypoxanthine phosphoribosyltransferase gene (HPRT) by deleting nucleotides often produced rearrangements at the target locus that in many cases were due to insertions of multimerized vector constructs, effectively converting a deletion vector into an insertion vector. These findings were obtained when adeno-associated virus vectors were used to efficiently deliver single-stranded DNA targeting constructs, but the same phenomenon was also observed when transfecting linearized double-stranded plasmids. Thus human cells distinguish between deletion and insertion vectors and process their recombination intermediates differently, presumably at the heteroduplex stage, with implications for the design of gene-targeting vectors and the evolution of human genomes.

| S-EPMC2940567 | biostudies-literature

Systematic discovery of complex insertions and deletions in human cancers.

Project description:Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.

| S-EPMC5003782 | biostudies-literature

Insertions and Deletions Target Lineage-Defining Genes in Human Cancers.

Project description:Certain cell types function as factories, secreting large quantities of one or more proteins that are central to the physiology of the respective organ. Examples include surfactant proteins in lung alveoli, albumin in liver parenchyma, and lipase in the stomach lining. Whole-genome sequencing analysis of lung adenocarcinomas revealed noncoding somatic mutational hotspots near VMP1/MIR21 and indel hotspots in surfactant protein genes (SFTPA1, SFTPB, and SFTPC). Extrapolation to other solid cancers demonstrated highly recurrent and tumor-type-specific indel hotspots targeting the noncoding regions of highly expressed genes defining certain secretory cellular lineages: albumin (ALB) in liver carcinoma, gastric lipase (LIPF) in stomach carcinoma, and thyroglobulin (TG) in thyroid carcinoma. The sequence contexts of indels targeting lineage-defining genes were significantly enriched in the AATAATD DNA motif and specific chromatin contexts, including H3K27ac and H3K36me3. Our findings illuminate a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer.

| S-EPMC5564321 | biostudies-literature

Probabilistic phylogenetic inference with insertions and deletions.

Project description:A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth-death) evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new "concordance test" benchmark on real ribosomal RNA alignments, we show that the extended program dnamlepsilon improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm.

| S-EPMC2527138 | biostudies-literature

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states.

Project description:The main principles of protein-protein recognition are elucidated by the studies of homooligomers which in turn mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell-cell adhesion processes. Here we explore oligomeric states of homologous proteins in various organisms to better understand the functional roles and evolutionary mechanisms of homooligomerization. We observe a great diversity in mechanisms controlling oligomerization and focus in our study on insertions and deletions in homologous proteins and how they enable or disable complex formation. We show that insertions and deletions which differentiate monomers and dimers have a significant tendency to be located on the interaction interfaces and about a quarter of all proteins studied and forty percent of enzymes have regions which mediate or disrupt the formation of oligomers. We suggest that relatively small insertions or deletions may have a profound effect on complex stability and/or specificity. Indeed removal of complex enabling regions from protein structures in many cases resulted in the complete or partial loss of stability. Moreover, we find that insertions and deletions modulating oligomerization have a lower aggregation propensity and contain a larger fraction of polar, charged residues, glycine and proline compared to conventional interfaces and protein surface. Most likely, these regions may mediate specific interactions, prevent nonspecific dysfunctional aggregation and preclude undesired interactions between close paralogs therefore separating their functional pathways. Last, we show how the presence or absence of insertions and deletions on interfaces might be of practical value in annotating protein oligomeric states.

| S-EPMC2996646 | biostudies-literature

Natural genetic variation caused by small insertions and deletions in the human genome.

Project description:Human genetic variation is expected to play a central role in personalized medicine. Yet only a fraction of the natural genetic variation that is harbored by humans has been discovered to date. Here we report almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans. These variants include 819,363 small INDELs that map to human genes. Small INDELs frequently were found in the coding exons of these genes, and several lines of evidence indicate that such variation is a major determinant of human biological diversity. Microarray-based genotyping experiments revealed several interesting observations regarding the population genetics of small INDEL variation. For example, we found that many of our INDELs had high levels of linkage disequilibrium (LD) with both HapMap SNPs and with high-scoring SNPs from genome-wide association studies. Overall, our study indicates that small INDEL variation is likely to be a key factor underlying inherited traits and diseases in humans.

| S-EPMC3106316 | biostudies-literature

Scanning for the signatures of positive selection for human-specific insertions and deletions.

Project description:Human-specific small insertions and deletions (HS indels, with lengths <100 bp) are reported to be ubiquitous in the human genome. However, whether these indels contribute to human-specific traits remains unclear. Here we employ a modified McDonald-Kreitman (MK) test and a combinatorial population genetics approach to infer, respectively, the occurrence of positive selection and recent selective sweep events associated with HS indels. We first extract 625,890 HS indels from the human-chimpanzee-macaque-mouse multiple alignments and classify them into nonpolymorphic (41%) and polymorphic (59%) indels with reference to the human indel polymorphism data. The modified MK test is then applied to 100-kb partially overlapped sliding windows across the human genome to scan for the signs of positive selection. After excluding the possibility of biased gene conversion and controlling for false discovery rate, we show that HS indels are potentially positively selected in about 10 Mb of the human genome. Furthermore, the indel-associated positively selected regions overlap with genes more often than expected. However, our result suggests that the potential targets of positive selection are located in noncoding regions. Meanwhile, we also demonstrate that the genomic regions surrounding HS indels are more frequently involved in recent selective sweep than the other regions. In addition, HS indels are associated with distinct recent selective sweep events in different human subpopulations. Our results suggest that HS indels may have been associated with human adaptive changes at both the species level and the subpopulation level.

| S-EPMC2817433 | biostudies-literature

Insertions/Deletions-Associated Nucleotide Polymorphism in Arabidopsis thaliana.

Project description:Although high levels of within-species variation are commonly observed, a general mechanism for the origin of such variation is still lacking. Insertions and deletions (indels) are a widespread feature of genomes and we hypothesize that there might be an association between indels and patterns of nucleotide polymorphism. Here, we investigate flanking sequences around 18 indels (>100 bp) among a large number of accessions of the plant, Arabidopsis thaliana. We found two distinct haplotypes, i.e., a nucleotide dimorphism, present around each of these indels and dimorphic haplotypes always corresponded to the indel-present/-absent patterns. In addition, the peaks of nucleotide diversity between the two divergent alleles were closely associated with these indels. Thus, there exists a close association between indels and dimorphisms. Further analysis suggests that indel-associated substitutions could be an important component of genetic variation shaping nucleotide polymorphism in Arabidopsis. Finally, we suggest a mechanism by which indels might generate these highly divergent haplotypes. This study provides evidence that nucleotide dimorphisms, which are frequently regarded as evidence of frequency-dependent selection, could be explained simply by structural variation in the genome.

| S-EPMC5127803 | biostudies-literature

Discovering sequence motifs with arbitrary insertions and deletions.

Project description:BIOLOGY IS ENCODED IN MOLECULAR SEQUENCES: deciphering this encoding remains a grand scientific challenge. Functional regions of DNA, RNA, and protein sequences often exhibit characteristic but subtle motifs; thus, computational discovery of motifs in sequences is a fundamental and much-studied problem. However, most current algorithms do not allow for insertions or deletions (indels) within motifs, and the few that do have other limitations. We present a method, GLAM2 (Gapped Local Alignment of Motifs), for discovering motifs allowing indels in a fully general manner, and a companion method GLAM2SCAN for searching sequence databases using such motifs. glam2 is a generalization of the gapless Gibbs sampling algorithm. It re-discovers variable-width protein motifs from the PROSITE database significantly more accurately than the alternative methods PRATT and SAM-T2K. Furthermore, it usefully refines protein motifs from the ELM database: in some cases, the refined motifs make orders of magnitude fewer overpredictions than the original ELM regular expressions. GLAM2 performs respectably on the BAliBASE multiple alignment benchmark, and may be superior to leading multiple alignment methods for "motif-like" alignments with N- and C-terminal extensions. Finally, we demonstrate the use of GLAM2 to discover protein kinase substrate motifs and a gapped DNA motif for the LIM-only transcriptional regulatory complex: using GLAM2SCAN, we identify promising targets for the latter. GLAM2 is especially promising for short protein motifs, and it should improve our ability to identify the protein cleavage sites, interaction sites, post-translational modification attachment sites, etc., that underlie much of biology. It may be equally useful for arbitrarily gapped motifs in DNA and RNA, although fewer examples of such motifs are known at present. GLAM2 is public domain software, available for download at http://bioinformatics.org.au/glam2.

| S-EPMC2323616 | biostudies-literature

Mapping insertions, deletions and SNPs on Venter's chromosomes.

Project description:BackgroundThe very recent availability of fully sequenced individual human genomes is a major revolution in biology which is certainly going to provide new insights into genetic diseases and genomic rearrangements.ResultsWe mapped the insertions, deletions and SNPs (single nucleotide polymorphisms) that are present in Craig Venter's genome, more precisely on chromosomes 17 to 22, and compared them with the human reference genome hg17. Our results show that insertions and deletions are almost absent in L1 and generally scarce in L2 isochore families (GC-poor L1+L2 isochores represent slightly over half of the human genome), whereas they increase in GC-rich isochores, largely paralleling the densities of genes, retroviral integrations and Alu sequences. The distributions of insertions/deletions are in striking contrast with those of SNPs which exhibit almost the same density across all isochore families with, however, a trend for lower concentrations in gene-rich regions.ConclusionsOur study strongly suggests that the distribution of insertions/deletions is due to the structure of chromatin which is mostly open in gene-rich, GC-rich isochores, and largely closed in gene-poor, GC-poor isochores. The different distributions of insertions/deletions and SNPs are clearly related to the two different responsible mechanisms, namely recombination and point mutations.

| S-EPMC2696090 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data